Affymetrix license valid, rules court.
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Biotechnology↗
Biomedical subjects
D Robertson
Publications and source records attributed to D Robertson.
Immunex takes premature step to guarantee Enbrel market share.
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Drug Industry↗
A technique for slicing the rat cochlea around the onset of hearing.
The cochlea presents a considerable challenge to the study of sound transduction and auditory neurotransmission. This arises from the location of the sensory, supporting and secretory epithelia, and primary auditory neurons within a complex ossified spiral structure comprised of three separate fluid-filled chambers. We have developed a novel cochlear slice preparation, which provides access to the highly differentiated tissues while retaining structural integrity and cell viability. Our technique for slicing the cochlea and imaging tissue structure facilitates the study of peripheral auditory signaling in situ. The preparation was developed in the neonatal rat (postnatal days 4-14) and is based on the use of vibrating blade microtome slicing after perfusing the perilymphatic compartments with chilled Pluronic F127 NF, a block copolymer gel. This material is liquid when cold, and sets when warmed to room temperature, stabilizing the cochlear fluid-filled compartments and thereby supporting the cochlear partition during slicing. Slices (150-300 microm) of neonatal rat cochlea, imaged using infrared videomicroscopy, allow tight-seal voltage clamp recordings from a variety of cell types. Recordings obtained from primary auditory neurons, hair cells, supporting cells, and Reissner's membrane epithelial cells verify the viability of the tissues in the preparation. Data includes novel evidence for glutamatergic and purinergic co-transmission by primary auditory neurons. The preparation has considerable potential in a range of molecular physiological applications requiring cell-specific targeting with retention of cell connectivity.
Animals↗
Distribution and possible functional roles of some neuroactive peptides in the mammalian superior olivary complex.
The mammalian superior olivary complex (SOC) is innervated by neuronal systems that contain a variety of neuroactive peptides. Conversely, neurones of the SOC form peptidergic projections to other targets. In this review, the peptides substance P, calcitonin-gene-related peptide, enkephalins and dynorphins, cholecystokinin and somatostatin are considered. Their distribution in fibres and cell bodies of the SOC are considered, with particular attention to differences between the SOC subdivisions. Evidence for the functional effects of these peptides is also reviewed and some brief speculations are offered about their possible functional role in hearing.
Animals↗
The neuropathic postural tachycardia syndrome.
BACKGROUND: The postural tachycardia syndrome is a common disorder that is characterized by chronic orthostatic symptoms and a dramatic increase in heart rate on standing, but that does not involve orthostatic hypotension. Several lines of evidence indicate that this disorder may result from sympathetic denervation of the legs. METHODS: We measured norepinephrine spillover (the rate of entry of norepinephrine into the venous circulation) in the arms and legs both before and in response to exposure to three stimuli (the cold pressor test, sodium nitroprusside infusion, and tyramine infusion) in 10 patients with the postural tachycardia syndrome and in 8 age- and sex-matched normal subjects. RESULTS: At base line, the mean (+/-SD) plasma norepinephrine concentration in the femoral vein was lower in the patients with the postural tachycardia syndrome than in the normal subjects (135+/-30 vs. 215+/-55 pg per milliliter [0.80+/-0.18 vs. 1.27+/-0.32 nmol per liter], P=0.001). Norepinephrine spillover in the arms increased to a similar extent in the two groups in response to each of the three stimuli, but the increases in the legs were smaller in the patients with the postural tachycardia syndrome than in the normal subjects (0.001+/-0.09 vs. 0.12+/-0.12 ng per minute per deciliter of tissue [0.006+/-0.53 vs. 0.71+/-0.71 nmol per minute per deciliter] with the cold pressor test, P=0.02; 0.02+/-0.07 vs. 0.23+/-0.17 ng per minute per deciliter [0.12+/-0.41 vs. 1.36+/-1.00 nmol per minute per deciliter] with nitroprusside infusion, P=0.01; and 0.008+/-0.09 vs. 0.19+/-0.25 ng per minute per deciliter [0.05+/-0.53 vs. 1.12+/-1.47 nmol per minute per deciliter] with tyramine infusion, P=0.04). CONCLUSIONS: The neuropathic postural tachycardia syndrome results from partial sympathetic denervation, especially in the legs.
Adult↗
Immunogold cytochemistry of the blood-brain barrier glucose transporter GLUT1 and endogenous albumin in the developing human brain.
The blood-brain barrier (BBB) glucose transporter, GLUT1, was detected by immunogold electron microscopy on the microvascular compartment of the human foetus telencephalon at the 12th and 18th weeks of gestation. By computerized morphometry, the cellular and subcellular localization of the immunosignal for GLUT1 was quantitatively evaluated. The study showed that the glucose transporter is strongly expressed by endothelial cells while a very low signal is detected on vascular pericytes. The GLUT1 antigenic sites are preferentially associated to the ablumenal and junctional plasma membranes of the endothelial cells and tend to increase significantly with age. A parallel study carried out by the endogenous serum protein albumin demonstrated that already at the 12th week the endothelial routes are hindered to the protein as happens at the blood-endothelium interface of mature brain. The results demonstrate that in the human foetus the brain microvessels express BBB-specific functional activities early.
Blood-Brain Barrier↗
A geminivirus replication protein interacts with the retinoblastoma protein through a novel domain to determine symptoms and tissue specificity of infection in plants.
Geminiviruses replicate in nuclei of mature plant cells after inducing the accumulation of host DNA replication machinery. Earlier studies showed that the viral replication factor, AL1, is sufficient for host induction and interacts with the cell cycle regulator, retinoblastoma (pRb). Unlike other DNA virus proteins, AL1 does not contain the pRb binding consensus, LXCXE, and interacts with plant pRb homo logues (pRBR) through a novel amino acid sequence. We mapped the pRBR binding domain of AL1 between amino acids 101 and 180 and identified two mutants that are differentially impacted for AL1-pRBR interactions. Plants infected with the E-N140 mutant, which is wild-type for pRBR binding, developed wild-type symptoms and accumulated viral DNA and AL1 protein in epidermal, mesophyll and vascular cells of mature leaves. Plants inoculated with the KEE146 mutant, which retains 16% pRBR binding activity, only developed chlorosis along the veins, and viral DNA, AL1 protein and the host DNA synthesis factor, proliferating cell nuclear antigen, were localized to vascular tissue. These results established the importance of AL1-pRBR interactions during geminivirus infection of plants.
Antigens, Polyomavirus Transforming↗
Sympathetically mediated hypertension in autonomic failure.
BACKGROUND: Approximately 50% of patients with primary autonomic failure have supine hypertension. We investigated whether this supine hypertension could be driven by residual sympathetic activity. METHODS AND RESULTS: In patients with multiple system atrophy (MSA) or pure autonomic failure (PAF), we studied the effect of oral yohimbine on seated systolic blood pressure (SBP), the effect of ganglionic blockade (with trimethaphan) on supine SBP and plasma catecholamine levels, and the effect of alpha(1)-adrenoreceptor blockade (phentolamine) on supine SBP. The SBP response to yohimbine was greater in patients with MSA than in those with PAF (area under the curve, 2248+/-543 versus 467+/-209 mm Hg. min; P=0.022). MSA patients with a higher supine SBP had a greater response than those with a lower supine SBP (3874+/-809 versus 785+/-189 mm Hg. min; P=0. 0017); this relationship was not seen in PAF patients. MSA patients had a marked depressor response to low infusion rates of trimethaphan; the response in PAF patients was more variable. Plasma norepinephrine decreased in both groups, but heart rate did not change in either group. At 1 mg/min, trimethaphan decreased supine SBP by 67+/-8 and 12+/-6 mm Hg in MSA and PAF patients, respectively (P<0.0001). Cardiac index and total peripheral resistance decreased in MSA patients by 33.4+/-5.8% and 40.7+/-9.5%, respectively (P=0. 0015). Patients having a depressor response to trimethaphan also had a depressor response to phentolamine. In MSA patients, the pressor response to yohimbine and the decrease in SBP with 1 mg/min trimethaphan were correlated (r=0.98; P=0.001). CONCLUSIONS: Residual sympathetic activity drives supine hypertension in MSA. It contributes to, but does not completely explain, supine hypertension in PAF.
Adrenergic alpha-Antagonists↗
Multiple system atrophy: the crime and the suspect.
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Humans↗
Oscillatory patterns in sympathetic neural discharge and cardiovascular variables during orthostatic stimulus.
BACKGROUND: We tested the hypothesis that a common oscillatory pattern might characterize the rhythmic discharge of muscle sympathetic nerve activity (MSNA) and the spontaneous variability of heart rate and systolic arterial pressure (SAP) during a physiological increase of sympathetic activity induced by the head-up tilt maneuver. METHODS AND RESULTS: Ten healthy subjects underwent continuous recordings of ECG, intra-arterial pressure, respiratory activity, central venous pressure, and MSNA, both in the recumbent position and during 75 degrees head-up tilt. Venous samplings for catecholamine assessment were obtained at rest and during the fifth minute of tilt. Spectrum and cross-spectrum analyses of R-R interval, SAP, and MSNA variabilities and of respiratory activity provided the low (LF, 0.1 Hz) and high frequency (HF, 0.27 Hz) rhythmic components of each signal and assessed their linear relationships. Compared with the recumbent position, tilt reduced central venous pressure, but blood pressure was unchanged. Heart rate, MSNA, and plasma epinephrine and norepinephrine levels increased, suggesting a marked enhancement of overall sympathetic activity. During tilt, LF(MSNA) increased compared with the level in the supine position; this mirrored similar changes observed in the LF components of R-R interval and SAP variabilities. The increase of LF(MSNA) was proportional to the amount of the sympathetic discharge. The coupling between LF components of MSNA and R-R interval and SAP variabilities was enhanced during tilt compared with rest. CONCLUSIONS: During the sympathetic activation induced by tilt, a similar oscillatory pattern based on an increased LF rhythmicity characterized the spontaneous variability of neural sympathetic discharge, R-R interval, and arterial pressure.
Adult↗
Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.
BACKGROUND: Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS: In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS: The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS: Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.
Adult↗
The pressor response to water drinking in humans : a sympathetic reflex?
BACKGROUND: Water drinking increases blood pressure profoundly in patients with autonomic failure and substantially in older control subjects. The mechanism that mediates this response is not known. METHODS AND RESULTS: We studied the effect of drinking tap water on seated blood pressure in 47 patients with severe autonomic failure (28 multiple system atrophy [MSA], 19 pure autonomic failure patients [PAF]). Eleven older controls and 8 young controls served as control group. We also studied the mechanisms that could increase blood pressure with water drinking. Systolic blood pressure increased profoundly with water drinking, reaching a maximum of 33+/-5 mm Hg in MSA and 37+/-7 in PAF mm Hg after 30 to 35 minutes. The pressor response was greater in patients with more retained sympathetic function and was almost completely abolished by trimethaphan infusion. Systolic blood pressure increased by 11+/-2.4 mm Hg in elderly but not in young controls. Plasma norepinephrine increased in both groups. Plasma renin activity, vasopressin, and blood volume did not change in any group. CONCLUSIONS: Water drinking significantly and rapidly raises sympathetic activity. Indeed, it raises plasma norepinephrine as much as such classic sympathetic stimuli as caffeine and nicotine. This effect profoundly increases blood pressure in autonomic failure patients, and this effect can be exploited to improve symptoms due to orthostatic hypotension. Water drinking also acutely raises blood pressure in older normal subjects. The pressor effect of oral water is an important yet unrecognized confounding factor in clinical studies of pressor agents and antihypertensive medications.
Aged↗
Orthostatic intolerance and the postural tachycardia syndrome: genetic and environment pathophysiologies. Neurolab Autonomic Team.
Orthostatic intolerance is a common problem for inbound space travelers. There is usually tachycardia on standing but blood pressure may be normal, low or, rarely, elevated. This condition is analogous to the orthostatic intolerance that occurs on Earth in individuals with orthostatic tachycardia, palpitations, mitral valve prolapse, and light-headedness. Our studies during the Neurolab mission indicated that sympathetic nerve traffic is raised in microgravity and that plasma norepinephrine is higher than baseline supine levels but lower than baseline upright levels. A subgroup of patients with familial orthostatic intolerance differ from inbound space travelers in that they have an alanine-to-to-proline mutation at amino acid position 457 in their norepinephrine transporter gene. This leads to poor clearance of norepinephrine from synapses, with consequent raised heart rate. Clinical features of these syndromes are presented.
Adrenergic Fibers↗
Morphological relationships of peptidergic and noradrenergic nerve terminals to olivocochlear neurones in the rat.
In the rat, the outer hair cells in the cochlea receive direct synaptic input from neurones in the ventral nucleus of the trapezoid body. These so-called medial olivocochlear neurones exert an inhibitory influence on the cochlear neural output. Electrophysiological in vitro studies suggest that the activity of medial olivocochlear neurones may be affected by a variety of neuropeptides as well as noradrenaline, but anatomical confirmation of direct synaptic input is still lacking. We have investigated, at the light microscopical level, the morphological relationships between terminals containing noradrenaline, substance P, cholecystokinin and leu-enkephalin, and medial olivocochlear neurones in the rat. A retrograde tracer was injected into the cochlea to label medial olivocochlear neurones and a double labelling immunocytochemical method was used to visualise the retrograde tracer as well as the neurotransmitters within each brain section. Light microscopical analysis revealed nerve endings containing substance P, cholecystokinin and leu-enkephalin in close apposition to the dendrites of medial olivocochlear neurones, and nerve endings containing dopamine-beta-hydroxylase, a marker for noradrenaline, in close contact with the somata as well as dendrites of medial olivocochlear neurones. Although the technique cannot prove the existence of functional synaptic contacts, the results are broadly consistent with electrophysiological data and suggest a direct input to medial olivocochlear neurones from substance P, cholecystokinin, leu-enkephalin and noradrenaline-containing neural pathways. Differences in the densities and spatial distribution of the various neuropharmacological inputs suggest differences in the relative strengths and possible roles of these diverse inputs to the olivocochlear system.
Animals↗
Evidence for direct cortical innervation of medial olivocochlear neurones in rats.
We have investigated the morphological relationship between auditory cortex efferents and medial olivocochlear neurones. Using combined retrograde and anterograde tracing we describe close contacts between medial olivocochlear neurones and corticofugal terminals in the ventral nucleus of the trapezoid body. The data indicate a possible direct action of the auditory cortex on the activity of the medial olivocochlear neurones and thus possibly the sensitivity of the cochlea.
Animals↗
Effects on cochlear responses of activation of descending pathways from the inferior colliculus.
The inferior colliculus (IC) has been shown anatomically to make direct descending connections with medial olivocochlear (MOC) neurones in the auditory brainstem. The MOC neurones project to the outer hair cells in the cochlea and inhibit cochlear neural output. This study investigated the effect of IC stimulation on cochlear output in both guinea pigs and rats in order to determine the functional significance of the IC-to-olivocochlear system projection. Stimulation of the central nucleus and the external cortex of the IC in paralysed guinea pigs, both contra- and ipsilaterally to the test cochlea, resulted in a small increase of the cochlear microphonic amplitude and a small decrease of the compound action potential (CAP) amplitude, the latter equivalent to a 3-6 dB change in acoustic input. Effects on the CAP were maximal in the frequency range 6-10 kHz. These effects were consistent with partial activation of the MOC system. In unparalysed rats, stimulation of the inferior colliculus evoked a large, prolonged suppression ranging from 5-12 dB in the amplitude of distortion product otoacoustic emissions (2f(1)-f(2); DPOAE), as reported previously by Scates et al. (1999). However, this suppression was decreased to only 0-3 dB when the animals were paralysed, suggesting that the larger suppression in the unparalysed state was the consequence of either a general masking effect caused by animal movement, or activation of middle ear muscles by the inferior colliculus stimulation. The results indicate a small but significant excitatory effect of the inferior colliculus on the medial olivocochlear system under conditions of anaesthesia and paralysis.
Action Potentials↗
Glutamic acid decarboxylase-positive neuronal cell bodies and terminals in the human cerebellar cortex.
The distribution of gamma-aminobutyric acid (GABA) in the human cerebellar cortex was studied using immunohistochemistry for glutamic acid decarboxylase (GAD), the enzyme that catalyses GABA synthesis. Observations by light microscopy revealed, in all layers of the cerebellar cortex, strong, punctate positivity for GAD, related to putative GABAergic nerve terminals, as well as a diffuse cytoplasmic immunoreactivity within neuronal cell bodies. GAD-positive nerve terminals were found in close relationship with the walls of the cerebellar cortex microvessels. Observations by electron microscopy revealed positive nerve terminals in contact with the astrocyte perivascular sheath of capillaries. GAD immunoreactivity was also detected within astroglial perivascular endfeet and endothelial cells. The findings provide further insights into the GABAergic synapses of the circuitry of the human cerebellar cortex. The detection of 'vascular' GAD immunoreactivities suggests that GABAergic mechanisms may regulate cerebellar microvessel function.
Aged↗
First round to Amgen in EPO battle.
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Erythropoietin↗